Soluble receptor-mediated selective inhibition of VEGFR and PDGFRbeta signaling during physiologic and tumor angiogenesis.

Abstract

The simultaneous targeting of both endothelial cells and pericytes via inhibition of VEGF receptor (VEGFR) and PDGFbeta receptor (PDGFRbeta) signaling, respectively, has been proposed to enhance the efficacy of antiangiogenic tumor therapy. Clinical and preclinical modeling of combined VEGFR and PDGFRbeta signaling inhibition, however, has used small molecule kinase inhibitors with inherently broad substrate specificities, precluding detailed examination of this hypothesis. Here, adenoviral expression of a soluble VEGFR2/Flk1 ectodomain (Ad Flk1-Fc) in combination with a soluble ectodomain of PDGFRbeta (Ad sPDGFRbeta) allowed highly selective inhibition of these pathways. The activity of Ad sPDGFRbeta was validated in vitro against PDGF-BB and in vivo with near-complete blockade of pericyte recruitment in the angiogenic corpus luteum, resulting in prominent hemorrhage, thus demonstrating an essential function for PDGF signaling during ovarian angiogenesis. Combination therapy with Ad PDGFRbeta and submaximal doses of Ad Flk1-Fc produced modest additive antitumor effects; however, no additivity was observed with maximal VEGF inhibition in numerous s.c. models. Notably, VEGF inhibition via Ad Flk1-Fc was sufficient to strongly suppress tumor endothelial and pericyte content as well as intratumoral PDGF-B mRNA, obscuring additive Ad sPDGFRbeta effects on pericytes or tumor volume. These studies using highly specific soluble receptors suggest that additivity between VEGFR and PDGFRbeta inhibition depends on the strength of VEGF blockade and appears minimal under conditions of maximal VEGF antagonism.

• Authors: Frank Kuhnert, Betty Y Y Tam, Barbara Sennino, John T Gray, Jenny Yuan, Angeline Jocson, Nihar R Nayak, Richard C Mulligan, Donald M McDonald, Calvin J Kuo
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 29 Pg. 10185-90 (Jul 22 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18632559 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• RNA, Messenger
• RNA, Neoplasm
• Recombinant Proteins
• Receptor, Platelet-Derived Growth Factor beta
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Adenoviridae (genetics)
• Animals
• Corpus Luteum (blood supply, cytology)
• Female
• Genetic Therapy
• Hemorrhage (etiology)
• Mice
• Mice, Inbred C57BL
• Neoplasms, Experimental (blood supply, genetics, therapy)
• Neovascularization, Pathologic
• Neovascularization, Physiologic
• Pericytes (cytology)
• RNA, Messenger (genetics, metabolism)
• RNA, Neoplasm (genetics, metabolism)
• Receptor, Platelet-Derived Growth Factor beta (antagonists & inhibitors, physiology)
• Recombinant Proteins (genetics, metabolism)
• Signal Transduction
• Solubility
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors, genetics, physiology)